Browsing by Author "Kaur, Raman Preet"

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    Analysis of pro‐ and anti‐inflammatory cytokine gene variants and serum cytokine levels as prognostic markers in breast cancer
    (Wiley, 2018) Kaur, Raman Preet; Vasudeva, Kanika; Singla, Heena; Benipal, Raja Paramjeet Singh; Khetarpal, Preeti; Munshi, Anjana
    The aim of current study was to evaluate the genetic variation in all the genes encoding pro‐ and anti‐inflammatory cytokines in association with breast cancer development in patients from Malwa region of Punjab. The importance of the levels of interleukin (IL)‐17, tumor necrosis factor, interferon γ, IL‐10, IL‐6, IL‐4, and IL‐2 with respect to clinicopathological data, prognosis, and disease‐free survival was also determined in these patients. Two hundred and fifty female breast cancer patients and 250 age‐matched controls were screened for variations in cytokine‐encoding genes using global screening array microchip and PCR‐RFLP. The level of cytokines was estimated in 150 patients and 60 age‐matched controls using BD™ Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit by BD Accuri flow cytometer. The difference in cytokine levels was evaluated by Mann–Whitney test. No significant variation in the genes encoding various cytokines was found between patients and controls. Out of the seven cytokines evaluated, the levels of IL‐6 and IL‐17a were found to be significantly high in patients in comparison with controls ( p = 0.001 and 0.02, respectively). The elevated levels of these cytokines are also associated significantly with poor outcome. We did not find any specific variation in the genes encoding various cytokines between patients and controls. However, there was a significant difference in the serum levels of IL‐6 and IL‐17a between patients and controls, and the elevated levels of these two cytokines associated significantly with poor outcome in breast cancer patients and, therefore, can be used as prognostic markers.
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    Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array
    (Springer Verlag, 2018) Kalra, Sourav; Kaur, Raman Preet; Ludhiadch, Abhilash; Shafi, Gowhar; Vashista, Rajesh; Kumar, Raj; Munshi, Anjana
    Purpose: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. Methods: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 ? 10?8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. Results: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. Conclusion: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy. ? 2018 Springer-Verlag GmbH Germany, part of Springer Nature
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    A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors.
    (Springer, 2018) Shalini, Anjali; Kaur, Raman Preet; Munshi, Anjana
    BRCA2is the main susceptibility gene known to be involved in the pathogenesis of breast cancer. It plays an important role in maintaining the genome stability by homologous recombination through DNA double-strand breaks repairing, by interacting with various other proteins including RAD51, DSS1, RPA, MRE11, PALB2, and p53. BRCA2-deficient cells show the abnormalities of chromosome number. BRCA2 is also found to be involved in centrosome duplication specifically in the metaphase to anaphase transition. Inactivation or depletion of BRCA2 leads to centrosome amplification that results in unequal separation of chromosomes. BRCA2 localizes with central spindle and midbody during telophase and cytokinesis. Inactivation or depletion of BRCA2 leads to multinucleation of cell. Around 2000 mutations have been reported in BRCA2 gene. BRCA2-deficient tumors are being taking into consideration for targeted cancer therapy by using different inhibitors like poly ADP-ribose polymerase and thymidylate synthase. The present review focusses on the role of BRCA2 in various critical cellular processes based on the mechanistic approaches. Mutations reported in the BRCA2 gene in various ethnic groups till date have also been compiled with an insight into the functional aspects of these alterations. The therapeutic strategies for targeting BRCA2-deficient tumors have also been targeted.
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    Epidemiological factors, genetic and inflammatory markers in the development of Breast Cancer in Malwa region of Punjab
    (Central University of Punjab, 2019) Kaur, Raman Preet; Munshi, Anjana
    Breast cancer is one of the most common malignancy among women and also the leading cause of death worldwide. Malwa region of Punjab is reported to have the highest number of cancer cases in comparison with the other two regions (Doaba and Majha). The cancer prevalence in this region was reported to be 1089 per million/year in 2013 (with around 35.7% breast cancer cases), as per the Department of Health and Family Welfare. The aim of present study was to carry out a systematic epidemiological study, explore the contribution of mutations in breast cancer susceptibility genes, and gene-gene interactions in the development of breast cancer in Malwa region of Punjab. In addition, exome sequencing of the male breast cancer patients was carried out to identify the specific genetic alterations associated with the disease in this region. Inflammatory markers (cytokines and C-reactive protein levels) and albumin levels were also estimated to evaluate their association with the development of the disease and outcome including death, recurrence, and metastasis. Three hundred breast cancer patients (Female:Male = 296:4) were recruited from Guru Gobind Singh Medical College & Hospital, Faridkot and Max Hospital, Bathinda. Equal number of age and sex matched controls were also recruited from the same demographic area with the help of Rural Medical Officers. The study was approved by the ethics committee of the Central University of Punjab. The information regarding the demographic profile was collected in a structured questionnaire. The blood samples were collected with the written informed consent of the patients. DNA isolation was carried out by phenol:chloroform method. The genotyping was performed by global screening array (GSA; Illumina Infinium HD), exome sequencing and PCRRFLP. The levels of inflammatory markers and albumin were estimated by using BD Accuri flow cytometer and ERBA 200 bioautoanlyzer. The association of demographic features with the disease was evaluated by Student’s t-test. Mann-Whitney test was used to evaluate the association of CRP, cytokines and albumin with the outcome. Softwares including R/Bioconductor and OpenEpi were used to evaluate the association of pathogenic alterations with the disease. The influence of novel mutations on protein structure was examined by molecular dynamics simulations. Follow-up of the patients was carried out with the help of clinicians. Infiltrating breast cancer was the most common type of breast cancer in patients. Triple negative breast cancer was observed in 17.5% of patients. All the patients underwent modified radical mastectomy and lumpectomy. The breast cancer patients v carried mono/biallelic alteration in 15 breast cancer susceptibility genes including ATM, BRCA2, STK11, PTEN, BRIP1, CHEK2, RAD51C, NBN, MLH1, MSH2, MSH6, MUTYH, CDK2NA, CYTB and MTHFR as per the results of GSA. Familial cases of breast cancer were found to carry alterations in ATM, BRCA2, STK11, PTEN, BRIP1, CHEK2, RAD51C, NBN, MLH1, MSH2, MSH6, MUTYH, CDK2NA, CYTB and MTHFR genes. Novel pathogenic variants in PALB2, STK11, CHEK2, BRCA2, BARD1, BRIP1, NF2, and FZR1 genes were detected in male breast cancer patients. These were found to alter the specific protein structure. Among the inflammatory markers CRP, IL-6 & IL17A were found to be significantly associated with poor outcome in the patients. High levels of albumin were also found to be associated with increased overall survival. In conclusion, results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations from Malwa region of Punjab. The present study suggests that the screening of BRCA2, MSH2, and MLH1 should be carried out in general population since previous studies have reported that these mutations increase the risk of breast cancer by 10-fold and accordingly evidence-based management recommendations can be given to the individuals bearing these mutations. Familial breast cancer patients need to be screened for BRAD1, MSH2, MLH1, BRCA2 and CYTB genes since these alterations were observed in familial breast cancer patients. IL-6, IL-17A, CRP, and albumin can be used as prognostic markers for breast cancer in Malwa region of Punjab.
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    Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients
    (Humana Press Inc., 2018) Kaur, Raman Preet; Shafi, Gowhar; Benipal, Raja Paramjeet Singh; Munshi, Anjana
    In this study, we evaluated the incidence of pathogenic germline mutations in 30 breast cancer susceptibility genes in breast cancer patients. Our aim was to understand the involvement of the inherited mutations in these genes in a breast cancer cohort. Two hundred ninety-six female breast cancer patients including 4.5% of familial breast cancer cases were included in the study. 200?ng of genomic DNA was used to evaluate the pathogenic mutations, detected using Global Screening Array (GSA) microchip (Illumina Inc.) according to the manufacturer?s instructions. The pathogenic frameshift and nonsense mutations were observed in BRCA2 (10.9%), MLH1 (58.6%), MTHFR (50%), MSH2 (14.2%), and CYTB (52%) genes. Familial breast cancer patients (4.5%) had variations in BRCA2, MLH1, MSH2, and CYTB genes. 28% of patients with metastasis, recurrence, and death harbored mono/biallelic alterations in MSH2, MLH1, and BRCA2 genes. The results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations, from Malwa region of Punjab. The screening of MSH2, MLH1, and BRCA2 should be carried in individuals with or without family history of breast cancer as these genes have been reported to increase the cancer risk by tenfold. ? 2018, Springer Science+Business Media, LLC, part of Springer Nature.
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    Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies
    (Elsevier Masson SAS, 2017) Singla, Heena; Ludhiadch, Abhilash; Kaur, Raman Preet; Chander, Harish; Kumar, Vinod; Munshi, Anjana
    HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. ? 2017 Elsevier Masson SAS
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    Role of p53 gene in breast cancer: Focus on mutation spectrum and therapeutic strategies
    (Bentham Science Publishers B.V., 2018) Kaur, Raman Preet; Vasudeva, Kanika; Kumar, Roshan; Munshi, Anjana
    TP53 is a tumor suppressor gene which is commonly mutated in various cancers including breast cancer. Alterations in the gene lead to an altered expression of various genes that are directly or indirectly under the transcriptional control of p53. This results in malfunctioning of DNA damage repair pathways, cell-cycle arrest, chromatin remodeling and apoptosis. Different mutations in TP53 gene have been reported in different ethnic groups and exon 4 and intron 3 are reported to be frequently mutated in breast cancer patients especially triple-negative breast cancer. Increased global burden of TP53 mutated breast tumors has paved the path for various therapies targeting p53/TP53. Numerous molecules including nutilins, MI series, RO5693, PRIMA-1, RITA, etc. have been developed. Majority of these restore p53/TP53 function by targeting negative regulators of p53/TP53, wtp53/TP53 (wild-type) and mtp53/TP53 (mutant). Most of these molecules are in the preclinical phase except for two APR-246 and COTI-2 that have progressed to clinical trials. The current review has been compiled with an aim to give an overview of mutations in p53 across various ethnic groups, the effect of these alterations on TP53 function and the therapeutic strategies developed till date targeting p53/TP53 especially in breast cancer.
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    Serum Albumin Levels in Breast Cancer: Correlation with Overall Survival
    (SciTechnol, 2017) Kaur, Raman Preet; Rubal; Dhiman, Monisha; Vashitstha, Rajesh; Munshi, Anjana
    Introduction: Albumin in an important biomarker that indicates malnutrition as well as inflammation. The aim of the study was to evaluate the albumin levels in breast cancer patients and its association with overall survival among breast cancer patients of Malwa region of Punjab. Material and methods: The study was planned in Malwa region of Punjab. Sampling was done from Guru Gobind Singh Medical College and Hospital and Max Hospital. The estimation of albumin levels was done at Central University of Punjab. 250 patients with breast cancer and 250 age and sex matched controls were involved in the study. Albumin levels were estimated using fully automated bio analyzer Erba 200. Follow-up interviews were conducted at an interval of 3, 6, 12 and 15 months to determine the outcome among breast cancer patients. Results: Low levels of albumin was found among the diseased in comparison with controls (p<0.000). Higher albumin levels associated significantly with overall survival in breast cancer patients [χ2: 11.95, p<0.000; odds ratio: 7.636 (95% CI, 2.047- 28.49)]. Conclusion: Elevated levels of albumin (>3.5 g/dl) are associated significantly with increased overall survival among breast cancer patients. Albumin estimation may be a simple and inexpensive tool for the risk assessment and outcome of the disease in Malwa region of Punjab where the incidence of breast cancer is reported to be very high.